Dysbiosis of gut microbiota—the microbes residing in the gastrointestinal tract—is linked to various metabolic and neurologic conditions such as diabetes, obesity and autism. This role in regulating host physiology is likely not only through metabolism of dietary substances such as fiber, but also via secreted microbial products that regulate host signaling pathways. To identify such microbe-derived molecules, Cohen et al. performed a bioinformatics analysis of human microbiome data to find bacterial enzymes that produce N-acyl amides, as this class of lipids interacts with G-protein-coupled receptors (GPCRs) that have been implicated in metabolic conditions. The authors identified 143 unique N-acyl synthase genes, which are enriched in gastrointestinal bacteria compared to bacteria from other host sites. Individual expression of 44 of these genes in Escherichia coli indicated that they produce N-acyl amides of six major families that are structurally similar to human GPCR ligands, including N-acyl serinol, which resembles the GPR119 ligand oleoylethanolamide. Profiling of one member of each of these families against 240 human GPCRs revealed strong and specific interactions, particularly among receptors expressed in the gastrointestinal tract. Mice colonized with bacteria expressing the synthase for N-acyl serinols showed reduced blood sugar levels in an oral glucose-tolerance test, consistent with action on host GPR119. These findings represent some of the first examples of microbe-derived small molecules affecting host physiology and highlight the use of functional metagenomics to identify important microbial effectors.